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Response to Dario Ringach

On April 9, 2010 in an Opposing Viewsopinion Dario Ringach, PhD of UCLA took me to task on several points. I will respond to these accusations here. A blog is not a scientific peer reviewed journal nor is it the proper forum for a lengthy response. Nevertheless, I will address the major points here and refer the reader to a more lengthy explanation as appropriate.

In his first paragraph Dr Ringach explains that what a model is. While he is right in what he confirms, that models can be used as approximations, he is wrong in what he denies. Animal models, as Shanks and I criticize them, are not used SIMPLY as approximations but as predictive models for human response to drugs and disease (see Animal Models in Light of Evolution for more detail on this) and in this they fail utterly. Neither Dr Shanks nor I have ever said that it is scientifically invalid to use animal models as heuristic devices, which is what Dr Ringach is referring to in his essay. For example, in Animal Models in Light of Evolutionwe state:

There can be no doubt whatsoever that if you wish to make discoveries about rats and mice you will be forced of methodological necessity to perform careful scientific studies of R. rattus and M. musculus respectively. In fact, in writing this book, we are the beneficiaries of the results of careful scientific studies of animals. There is no doubt that careful biological studies of rats and mice can help clarify the general contours of mammalian biology. Such studies can also play a valuable heuristic role by prompting new ways of thinking about human biological problems of interest. The issue we are concerned with is this: notwithstanding these cautions, are animal models predictive of human outcomes in, say, toxicology, drug discovery, and the study of the causes and cures of human diseases? [p28]

We continue this theme:

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The genome projects vindicate Darwin: monkeys, mice and men belong to different species, but they are not rankable in order of relative complexity. The idea that humans are more complex than other mammals has been remarkably persistent. And this is true in the animal model community when theorists engaged in basic biomedical research (as opposed to predictive animal modeling) claim that their animal models are good systems to study with respect to the heuristics of human biology because they are in some sense simpler systems . . . Some animal modelers have had similar ideas concerning the use of nonhuman mammals as heuristic devices to prompt hypotheses about human biomedical phenomena. Forni et al. (1990) have reflected on the value of rodent cancer models using highly immunogenic tumors, which are very rare features of the human oncological condition, by observing:

This is made possible by reducing the complex problem to simpler models in which some features of the situation they reflect are deliberately ignored. The use of highly immunogenic tumors in these studies is fully justified by the fact that currently we still have only a vague idea of the cell mechanisms involved in immune resistance to tumors. (Forni et al. 1990)

Such models are clearly intended to be suggestive, not predictive models, and as Forni et al. caution:

Of course the use of models can be dangerous. Some biological functions that appear to be crucial to a simplified system may lose their importance or take on a different meaning in more complex systems. The fact that it is a model, not the real situation, that is being studied may be forgotten.” (Forni et al. 1990)

In point of fact, immunogenic tumors in rodents are not simpler than human tumors; rather they are different (and possibly more amenable to study and to treat). It would be a mistake to assume that ease of generation, and amenability to study, are marks of fundamental biological simplicity, at least as that might be understood with respect to putative complexity-based phylogenetic ordering schemes. [p337-8]

The above is pretty clear! We do not present a global dismissal of all experiments on animals in science as being scientifically useless (we are not stupid whatever else we may be). We do, however, offer criticisms, based on scientific evidence, of the use of animal models as predictive devices. Animal Models in Light of Evolution explains this in detail. To give just example:

In this book, we present a critical analysis of the use of animals in the context of biomedical research aimed at predicting human responses with respect to such matters as the study of disease, the safety of pharmaceutical products, and the effects of environmental toxins. We will raise concerns about the clinical relevance of predictive animal modeling. [p21]

To accuse us of taking a position we do not in order to then refute it is a straw man fallacy. This is even more regrettable in Dr Ringach’s case as he, Shanks, and I just participated in a panel discussion outlining and explaining our views and Shanks was very clear on this point about criticism of the use of animals as predictive models.

Now is a good time to address an issue that frequently crops up in the context of discussions of these contentious matters. Because we make extensive use of quotations we run the risk of being accused of taking the words of others out of context. This is an easy accusation to make, but without carefully reasoned backing, the accusation, in and of itself, is little more than an indication of intellectual laziness. Sometimes, of course, accusations of this kind are indeed justified and can be defended by citing additional evidence. Without credible supporting evidence, the accusation that someone has taken something out of context is largely empty. Its main function is to immunize what was quoted from scrutiny in the court of rational inquiry.

The issue here is not whether the authors we quote agree with our overall point of view (or indeed with any of it) but whether what they said was what we reported. We quote the words of animal modelers who have admitted in print, in publicly checkable sources, that there are methodological and evidential problems associated with the claim that experiments on nonhuman animals can be used to predict human responses (regardless of whatever else animals are useful for in science). That many of these same researchers believe that animals can be used to predict human responses is, with no further discussion, neither here nor there. We discuss at length the theoretical reasons given to justify predictive uses of animal models, and we criticize these justifications in due course. Our point is that the prediction issue is on the table for discussion.

Many of the scientists we quote are speaking very specifically about an area or example that falls directly within their expertise. When they comment that animal models failed in some way, in their area of expertise, their claim carries weight no matter how committed they are to the use of animals in biomedical research!

The FACTS of species differences relevant to the prediction issue are not in question. What is at issue are the INTERPRETATIONS authors place on the facts they refer to. We are justified in citing facts (and quoting researchers who do so) while rejecting interpretations. We cite many examples of the same phenomenon (species difference) to establish that it is a more or less agreed fact. Our point is not to get involved in an endless dingdong about examples but to suggest that there are other well-established ways to deal with what we see (i.e. evolutionary biology). It matters not to us that those referring to the facts of species differences are also ardent advocates of animal experimentation. What matters are the facts, along with consideration of alternative hypotheses about their significance. We will offer some alternative hypotheses about the significance of the facts we uncover. Science, after all, is as much driven by disputes about the meaning and significance of facts as it is about the facts themselves. We have nothing to apologize for in this regard. [p27]

We were very clear in the book Ringach cited that scientists (mainly in professional communications, but sometimes in popular literature) will acknowledge the fact of the existence of important (evolved) differences between species. These claims, and the reasons given by way of explanation, are of great interest to those working on the animal prediction issue. It is irrelevant that those who make the admissions and provide the rationales for them also believe animals are scientifically useful in other contexts. They will get no argument from us on this, but neither is the point relevant to the predictive issue at hand!

As to Dr Weinberg’s comments that my “agenda” means no more cures I will just say that such hyperbole in addition to misrepresenting reality brings nothing positive to the discussion. I have never said nor implied that the study of humans and mice were mutually exclusive but have pointed out the fact that for every NIH dollar a mouse model of cancer receives that is one dollar that will not go to the study of human cancer. Perhaps Dr Weinberg would like to accuse Fortune magazine of misquoting him or quoting him out of context in their 2004 article titled “Why We’re Losing the War on Cancer”:

The cancer community has published an extraordinary 150,855 experimental studies on mice, according to a search of the PubMed database. Guess how many of them have led to treatments for cancer? Very, very few. In fact, if you want to understand where the War on Cancer has gone wrong, the mouse is a pretty good place to start. Says Weinberg: “A fundamental problem which remains to be solved in the whole cancer research effort, in terms of therapies, is that the preclinical [animal] models of human cancer, in large part, stink” . . . Even more depressing is the very real possibility that reliance on this flawed model has caused researchers to pass over drugs that would work in humans. After all, if so many promising drugs that clobbered mouse cancers failed in man, the reverse is also likely: More than a few of the hundreds of thousands of compounds discarded over the past 20 years might have been truly effective agents. Roy Herbst, who divides his time between bench and bedside at M.D. Anderson and who has run big trials on Iressa and other targeted therapies for lung cancer, is sure that happens often. “It’s something that bothers me a lot,” he says.

In Animal Models in Light of Evolutionwe go into great detail about why curing cancer in mice will not of itself lead to cures for cancer in humans. I suggest the reader actually read the entire book and decide for himself whether we are misrepresenting reality.

Finally, let me again state that a blog is not an adequate venue for deciding these issues. Two forums have historically been used, as there are essentially two communities involved in this very important issue. The scientific community should take the lead and allow discussion in the peer review scientific journals. An open debate should be encouraged. Historically this has not even been allowed, as the editors have not wanted to let our side be heard. I remind the reader of the following from Herbert Spencer: “There is a principle which is a bar against all information, which is proof against all arguments and which cannot fail to keep a man in everlasting ignorance - that principle is contempt prior to investigation.” I challenge the editors to live up to the principles of science and the scientific method and allow a thorough debate on this issue. The taxpayers who fund a lot of this research deserve more from scientists than mere spin, name-calling and verbal abuse when questions are raised about the scientific justifications for their publicly funded research.

I have on several occasions asked scientists who disagree with me to participate in a Point-Counterpoint discussion in a peer reviewed indexed journal that is willing to host such a discussion. This would allow both sides a fair forum to present their positions. To date, no scientist has taken that offer preferring instead to fill the web with unsubstantiated vitriol. (For more on this see Response to Orac.) I offer the same to Dr Ringach.

The second party with an interest in this issue is society in general. If what we are saying is true, the FDA and EPA should dramatically change their regulations and the NIH should equally dramatically alter their funding priorities. Society is paying for the status quo both in terms of taxpayer dollars and lives when needed cures are not forthcoming. Going as far back as the Revolutionary War, Americans have witnessed controversial issues debated in public forums and walked away better able to judge the issue for themselves. I have repeatedly been assured by Drs Ringach and Jentsch of UCLA that they desire a public debate or even a series of debate on these issues. Our understanding was that the first debate would be this Spring on the role of animals as predictive models in science. But despite their promises, NO such an event has been forthcoming.

I again challenge Drs Ringach and Jentsch to make good on their promise to debate these issues. In light of society’s lack of understanding of science and the scientific method vis-à-vis the high percentage that does not accept evolution, believes in astrology, homeopathy, and so forth, scientists should be taking every opportunity to make their case both for science in general and for whatever controversial position they hold in particular. Society will benefit regardless of the outcome.